Mechanochemical synthesis of primary amides from carboxylic acids using TCT/NH4SCN

Article abstract of DOI:10.1016/j.tetlet.2018.08.035

A facile and effective approach toward the synthesis of primary amides from carboxylic acids has been developed. In the presence of 2,4,6-trichloro-1,3,5-triazine, a combination of ammonium thiocyanate and potassium carbonate led to the rapid conversion of carboxylic acids into the corresponding amides within five minutes grinding at room temperature. The use of ammonium thiocyanate as the amine source is unprecedented and exclusive formation of primary amides is observed only under the liquid-assisted grinding conditions.

Full text of DOI:10.1016/j.tetlet.2018.08.035

Accepted Manuscript
Mechanochemical synthesis of primary amides from carboxylic acids using
TCT/NH4SCN
Subin Jaita, Wong Phakhodee, Neeranuch Chairungsi, Mookda Pattarawarapan
PII:
S0040-4039(18)31027-X
https://doi.org/10.1016/j.tetlet.2018.08.035
TETL 50210
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 July 2018
9 August 2018
20 August 2018
Please cite this article as: Jaita, S., Phakhodee, W., Chairungsi, N., Pattarawarapan, M., Mechanochemical synthesis
of primary amides from carboxylic acids using TCT/NH4SCN, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.08.035
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Mechanochemical synthesis of primary amides from carboxylic acids using
TCT/NH4SCN
Subin Jaita,a Wong Phakhodee,b,c Neeranuch Chairungsi,d and Mookda Pattarawarapan b,c*
aFaculty of Science and Agricultural Technology, Rajamangala University of Technology
Lanna Chiang Rai, Chiang Rai 57120 Thailand
bDepartment of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200,
Thailand
cResearch Center on Chemistry for Development of Health Promoting Products from
Northern Resources, Chiang Mai University, Chiang Mai, 50200, Thailand
dDepartment of Chemistry, Faculty of Science and Technology, Chiang Mai Rajabhat
University, Chiang Mai, 50300, Thailand
To whom correspondence should be addressed.
Department of Chemistry,
Faculty of Science,
Chiang Mai University,
Chiang Mai
50200
Thailand
Tel. +66 5394 3341
Fax. +66 5389 2277
e-mail: mookdap55@gmail.com

Abstract
A facile and effective approach toward the synthesis of primary amides from carboxylic acids
has been developed. In the presence of 2,4,6-trichloro-1,3,5-triazine, a combination of
ammonium thiocyanate and potassium carbonate led to the rapid conversion of carboxylic
acids into the corresponding amides within five minutes grinding at room temperature. The
use of ammonium thiocyanate as the amine source is unprecedented and exclusive formation
of primary amides is observed only under the liquid-assisted grinding conditions.
Keywords: Carboxylic acid; Cyanuric chloride; Amide; Ammonium thiocyanate;
Mechanosynthesis
Introduction
Primary amides are prevalent in natural products, pharmaceuticals, and bioactive
molecules.1 Moreover, they are versatile precursors and intermediates in the synthesis of
various valuable products.2 Although a number of nonclassical routes toward primary amides
have been developed starting from carboxylic acid derivatives,3 nitriles,4 aldoximes,5
aldehydes,6 alkynes,7 alcohols,8 amines,9 or aryl iodides,10 these methods generally require
expensive catalysts, harsh reaction conditions, long reaction times, and have limited substrate
scope.
While several problems remain to be overcome, the classical condensation of
ammonia with acyl chlorides or with carboxylic acids in the presence of an activator appears
to be the most straightforward route for primary amide synthesis. This could be due to
advantages such as readily available and less expensive materials, mild reaction conditions,
and a broad range of functional group compatibility.11
Nevertheless, due to its weak basicity, gaseous nature, and low solubility in organic
solvents, the direct use of ammonia is not ideal and often requires high-pressure reactors. To
minimize the safety hazard, volatile ammonia could be replaced with easier to handle, less
toxic, and inexpensive ammonium salts. Whereas the application of ammonium salts such as
14
NH4Cl,12 NH4OAc,13 NH4HCO3 have been reported in amide bond formation, the use of

ammonium thiocyanate (NH4SCN) has never been explored, possibly due to the potential for
side-reactions such as thiocyanation and the formation of acyl isothiocyanates.15
Although waste management has become a major issue in modern industry, the
majority of available organic reactions still rely mainly on solution-phase chemistry
involving the use of a large excess of volatile organic solvent and highly toxic chemicals.
Thus, it is desirable to develop more environmentally friendly processes using safer reagents,
requiring fewer synthetic steps, with minimal use of organic solvents.16 In this regard,
mechanochemical synthesis, especially those carried out with the addition of a small amount
of solvent (so called liquid-assisted grinding (LAG) or solvent drop grinding) has been
increasingly adopted as an alternative greener protocol.17 This technique offers several
benefits in terms of energy efficiency, selectivity, ease of operation, and solvent reduction.
In continuation of our studies on the use of 2,4,6-trichloro-1,3,5-triazine (TCT) as an
activator of carboxylic acids, various LAG conditions using less toxic and easy to handle
inorganic bases have been investigated.18 Herein, we report a simple, rapid, and high yielding
TCT-mediated mechanochemical synthesis of primary amides from carboxylic acid using
NH4SCN as an ammonia source.
Results and Discussion
Initially, benzoic acid was chosen as the model substrate to optimize the reaction
conditions including the type of ammonium salts as the source of ammonia, solvents, and
energy input method (Table 1). The reaction under LAG conditions was typically carried out
by mixing benzoic acid and TCT which were ground together using a mortar and pestle in the
presence of potassium carbonate (2 equiv.) and a few drops of THF (calculated to be less than
1 L/mg of solids). After one minute, the time at which the starting acid was completely
consumed, the ammonium salt (1.2 equiv.) was added, followed by grinding for five minutes.
The reaction of benzoic acid with NH4I or NH4Br gave benzamide 1a in good yields
(Entries 1-2). However, other ammonium salts were less effective (Entries 3-5). Interestingly,
the best result was obtained with NH4SCN leading to the exclusive formation of 1a in high
yield without detectable side-products from thiocyanation (Entry 6).

Considering the weak nucleophilicity of ammonia compared to the thiocyanate or
isothiocyanate ion, the obtained result is unexpected, especially since aroylthiocyanates can
be derived from carboxylic acids using the TCT/Et3N/NH4SCN combination.15f Therefore, a
further experiment was carried out using KSCN instead of NH4SCN. Only benzoic anhydride
and some remaining starting material were detected without formation of the corresponding
acyl isothiocyanate. This led us to postulate that under the grinding conditions where the
inorganic base and the ammonium salt are not entirely soluble, the anion (SCN-) could be
protonated and exist in the form of thiocyanic acid (HSCN) or mainly as its tautomer,
isothiocyanic acid (HNCS), which did not react with the formed activated triazine ester. The
decomposition of ammonium thiocyanate to H2S is highly unlikely as the formation of
ammonia, hydrogen sulfide, and carbon disulfide proceeds upon prolong heating at high
temperature. However, heat generated from friction may cause the thiocyanate to isomerize
into thiourea which makes the reagent ineffective as a thiocyanating agent.19
The effect of the solvent added during grinding was further compared. According to
entries 6-10, the reaction in THF was more efficient than those using other solvents. When
the reaction conditions in entry 6 was applied under conventional stirring or under sonication
in an ultrasonic bath, the reaction was incomplete and benzoic anhydride was obtained as a
major product along with benzamide in much lower yields (Entries 11-12). This data
indicates that the grinding process plays an essential role in altering the reaction path and
product selectivity, possibly through efficient mixing with an increased contact surface area
between the solid reagent and the reactants.20
Table 1. Optimization of the reaction conditionsa
O
O
TCT (0.4 equiv.)
NH2
OH
+
NH4X
K2CO3 (2 equiv.), 5 min
(1.2 equiv.)
1a
(1 equiv.)
Entry
1
NH4X
Solvent
THF
Method
grinding
grinding
grinding
grinding
grinding
grinding
grinding
grinding
grinding
grinding
stirring
Yield (%)
75
90
38
21
66
95
NR
85
20
18
23
35
NH4I
NH4Br
NH4Cl
2
THF
3
THF
4
THF
(NH4)2SO4
(NH4)2CO3
NH4SCN
NH4SCN
NH4SCN
NH4SCN
NH4SCN
NH4SCN
NH4SCN
5
THF
6
THF
7
EtOH
acetone
CH2Cl2
toluene
THF
8
9
10
11
12
THF
sonication

aReagents and conditions: benzoic acid (0.066 g, 0.542 mmol), TCT
(0.040 g, 0.216 mmol), K2CO3 (1.084 mmol), NH4X (0.650 mmol).
With the optimized reaction conditions in hand (Table 1, entry 6), we then turned our
attention to evaluating the scope and limitations of the protocol using a variety of carboxylic
acids. The reaction time was constant for all substrates so that the product yields would
reflect the reactivity of the substrates under the applied conditions.
According to Table 2, electron-rich substrates tend to give the amide products in
higher yields when compared with substrates containing electron-withdrawing groups
(Entries 1-10). Additionally, naphthanoic acids and aliphatic carboxylic acids were smoothly
converted into the corresponding primary amides with satisfying results (Entries 11-16). In
the reaction with an α,-unsaturated acid such as cinnamic acid (Entry 17), only the amide
was isolated without formation of the Michael addition product. These conditions are also
compatible with the Fmoc protecting group which is sensitive to aminolysis (Entry 18).
Moreover, the reaction took place within five minutes at room temperature instead of several
hours using other solution-based stirring conditions.21 Interestingly, in all experiments, the
amide products were exclusively obtained without detectable formation of other potential
side-products such as anhydrides, acyl isothiocyanates, or those derived from thiocyanation
of the benzene ring.
It should be noted that although the synthesis of primary amides from carboxylic
acids has previously been carried out under solvent-free conditions, such as those using
silica-supported ammonium chlorides/TsCl/Et3N12d or NH4Cl/SiO2-TCT/Et3N,12c our protocol
is more straightforward and does not involve supported reagents which require extra
preparation steps nor the excess use of a toxic organic base.
Table 2. TCT-mediated synthesis of primary amides
O
O
TCT, K2CO3
+
NH4SCN
R
OH
R
NH2
grinding, 5 min
1
Entry
1
R-
Amide 1
1a
Yield (%)
95
C6H5-

2
3
4-MeOC6H4-
4-MeC6H4-
4-ClC6H4-
1b
1c
1d
1e
1f
99
94
89
85
69
98
98
91
71
90
97
95
4
5
4-BrC6H4-
4-NO2C6H4-
2-MeOC6H4-
2-MeC6H4-
2-ClC6H4-
6
7
1g
1h
1i
8
9
10
11
12
13
2-NO2C6H4-
1-naphthyl
2-naphthyl
1j
1k
1l
1m
14
15
1n
1o
78
88
OCH3
16
1p
98
17
18
1q
1r
90
86
O
O
N
H
aReagents and conditions: carboxylic acid (0.542 mmol),
TCT (0.040 g, 0.216 mmol), K2CO3 (0.150 g, 1.084
mmol), THF (< 1 L/mg solids), 1 min, then NH4SCN
(0.045 g, 0.650 mmol), 5 min.
Conclusion
In summary, a rapid, facile, and efficient method for the preparation of primary
amides directly from carboxylic acids has been developed. This procedure represents the first
example utilizing ammonium thiocyanate for the in situ–generation of ammonia in an
amidation reaction. Such a reagent can be used as an alternative ammonia source, especially

when the reaction is ineffective using other ammonium salts. The exclusive formation of
primary amides without other side reactions under mechanochemical synthesis is also
noteworthy and further investigation on this type of reaction is underway.
Acknowledgements
We wish to thank the National Research University Project under Thailand’s Office of the
Higher Education Commission for financial support for S. J. Partial support from the Center
of Excellence for Innovation in Chemistry (PERCH-CIC), Chiang Mai University, Thailand
are also gratefully acknowledged.
Supplementary data
Experimental details and 1H NMR spectra for all products are available. Supplementary data
related to this article can be found at http://xxx.
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Highlights
 Direct synthesis of primary amides from carboxylic acids is reported.
 The reaction proceeded rapidly using TCT/NH4SCN under grinding.
 Amides were afforded in high yields with functional group tolerant.
22.
Graphical Abstract

Leave this area blank for abstract info.
Mechanochemical synthesis of primary amides from
carboxylic acids using TCT/NH4SCN
Subin Jaita, Wong Phakhodee, Neeranuch Chairungsi, and Mookda Pattarawarapan*
O
O
O
O
N
R
O
mortar & pestle
TCT, K2CO3, THF
1 min
mortar & pestle
R
OH
R
NH2
O
N
N
O
NH4SCN
5 min
18 examples
(69-99%)
R
O
R
O
R
NCS
not observed
23.